Study of so-called broad spectrum cephem compounds having potent antibacterial activities against various Gram-positive and Gram-negative bacteria has recently been focused on cephem compounds wherein the 7-side chain is substituted with aminothiazole or aminothiadiazole and the 3-position with a cyclic-type quarternary ammoniummethyl group. For example, the known 7-aminothiazole types include cefepime hydrochloride (U.S. Pat. No. 4,406,899), cefpirome sulfate (U.S. Pat. No. 4,609,653, JP(A) S57-192394), and cefoselis sulfate (JP(A) H07-196665, WO97/41128), and the 7-aminothiadiazole types include cefclidin (U.S. Pat. No. 4,748,171), and cefozopran hydrochloride (U.S. Pat. No. 4,864,022, JP(A) S62-149682, JP(A) H03-47189). Such types of cephem compounds are also reported in JP Patent publication (Kokai) S-58-4789 which discloses compounds having an “optionally substituted 2 or more of N atoms-containing heterocycle cation group” at the 3-position and in JP Patent publication (Kokai) S-60-155183 which discloses compounds having a “2 or more of N atoms-containing unsaturated condensed heterocyclic cation group” at the 3-position.
Documents such as JP Patent publication (Kokai) S-60-97982, JP Patent publication (Kokai) S-59-130294, JP Patent publication (Kokai) S-60-34973, JP Patent publication (Kokai) S-62-114990, JP Patent publication (Kokai) S-64-42491, and WO87/06232 etc. disclose cephem compounds which have a halogen on an aminothiazole ring at the 7-position or which are substituted with COOH at the end of the oxime part on the 7-side chain. These documents do not disclose a cephem compound having the both structural characteristics.
A cephem compound, which has a halogen on an aminothiazole ring at the 7-position and is substituted with COOH at the end of the oxime part on the 7-side chain, is known in JP Patent publication (Kokai) S-60-231684. However, a specifically disclosed compound is that wherein the methylene group bonding to the oxime part on the 7-side chain is non-substituted or dimethyl-substituted type. JP Patent publication (Kokai) S-57-131794 and JP Patent publication (Kokai) H-1-308286 discloses compounds wherein the methylene group bonding to the oxime part on the 7-side chain is substituted with monomethyl, however, the configuration is not specified and a quarternary ammonium group is not disclosed as a possible substituent on the methylene group at the 3-position. Further, any antibacterial activities against cephem-resistant Pseudomonas aeruginosa are not described therein.
A cephem compound having a quarternary ammonium group at the 3-position and a side chain of aminothiazole/oxime type at the 7-position, so-called broad spectrum antibacterial-type cephem, is known as being efficatious against G(−) bacteria including Pseudomonas aeruginosa. For example, ceftazidime has been reported as being stable against β-lactamase and possesing a relatively potent activity against β-lactamase-producing Pseudomonas aeruginosa(Acta Microbiologica Hungarica 35 (4), pp. 327-359 (1988)).
Under the above circumstances, among G(−) bacteria, the number of bacteria resistant to some broad spectrum antibacterial-type cephems has recently increased. The frequency of clinical isolation of cephem-resistant Pseudomonas aeruginosa, which highly produce β-lactamase, esp. Class C-type β-lactamase, has raised, which is recognized as a social problem worldwide (“Classification and Epidemiology of Recent β-lactamase”. Clinic and Microorganism Vol. 26 No. 2 1999.3 P103-109). However, a cephem compound with a potent activity against such cephem-resistant Pseudomonas aeruginosa has not been reported.
Therefore, the development of a novel cephem compound with broad antibacterial spectrum, preferably a compound possessing a potent activity against cephem-resistant Pseudomonas aeruginosa which produce β-lactamase has been desired. In preference, such a compound is useful as an injection.